Eutectic formulations of cyclobenzaprine hydrochloride and amitriptyline hydrochloride

ABSTRACT

The present invention relates to pharmaceutical compositions and methods of manufacturing the same, comprising a eutectic of Cyclobenzaprine HCl and mannitol or Amitriptyline HCl and mannitol.

RELATED APPLICATION

This application claims priority and benefit from U.S. ProvisionalPatent Application 61/792,757, filed Mar. 15, 2013, the contents anddisclosures of which are incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

Cyclobenzaprine, or3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine, wasfirst approved by the U.S. Food and Drug Administration in 1977 for thetreatment of acute muscle spasms of local origin. (Katz, W., et al.,Clinical Therapeutics 10:216-228 (1988)). Amitriptyline, or3-(10,11-dihydro-5H-dibenzo [a,d]cycloheptene-5-ylidene)-N,N-dimethyl-1-propanamine, was first approvedby the U.S. Food and Drug Administration for the treatment ofdepression.

Subsequent studies have shown cyclobenzaprine to also be effective inthe treatment of fibromyalgia syndrome, post-traumatic stress disorder(PTSD), traumatic brain injury (TBI), generalized anxiety disorder anddepression. Furthermore, the utility of cyclobenzaprine as an agent forimproving the quality of sleep, as a sleep deepener, or for treatingsleep disturbances has been investigated. However, while FDA-approvedtherapeutics address pain and mood, there are currently no FDA-approvedtreatments that address the disturbed sleep and fatigue associated withfibromyalgia syndrome. Treatment with cyclobenzaprine may beparticularly useful in treating sleep disturbances caused by,exacerbated by, or associated with fibromyalgia syndrome, prolongedfatigue, chronic fatigue, chronic fatigue syndrome, a sleep disorder, apsychogenic pain disorder, chronic pain syndrome (type II), theadministration of a drug, autoimmune disease, stress or anxiety, or fortreating an illness caused by or exacerbated by sleep disturbances, andsymptoms of such illness. See, for example, U.S. Pat. Nos. 6,395,788 and6,358,944, incorporated herein by reference.

Cyclobenzaprine HCl or Amitriptyline HCl Active PharmaceuticalIngredients (or APIs) are stable in pill, tablet or capsule formulationsfor oral administration when combined with certain excipients. However,Cyclobenzaprine HCl or Amitriptyline HCl have slow absorption wheningested by mouth (per oral, or po). To speed absorption, tabletscontaining Cyclobenzaprine HCl or Amitriptyline HCl have been formulatedin various sublingual (SL) preparations. However, both sublingual andoral formulations can have issues with the stability of the APIs and thephysical compositions themselves, especially when a basifying agent (achemical compound that increases the pH of solutions after dissolutionof Cyclobenzaprine HCl or Amitriptyline HCl) is present. Therefore, amethod or composition that increases stability of Cyclobenzaprine HCl orAmitriptyline HCl (with or without the presence of a basifying agent) ina formulation would be useful.

SUMMARY OF THE INVENTION

Some embodiments of the invention are:

1. A pharmaceutical composition comprising a eutectic of mannitol andCyclobenzaprine HCl.2. The pharmaceutical composition of embodiment 1, wherein the eutecticmixture melts at 143.6±3° C.3. The pharmaceutical composition of embodiment 1, comprising 60%-90%Cyclobenzaprine HCl and 40%-10% mannitol.4. The pharmaceutical composition of embodiment 3, comprising amounts ofCyclobenzaprine HCl and mannitol selected from: 60%±2% CyclobenzaprineHCl and 40%±2% mannitol, 65%±2% Cyclobenzaprine HCl and 35%±2% mannitol,70%±2% Cyclobenzaprine HCl and 30%±2% mannitol, 75%±2% CyclobenzaprineHCl and 25%±2% mannitol, 80%±2% Cyclobenzaprine HCl and 20%±2% mannitol,85%±2% Cyclobenzaprine HCl and 15%±2% mannitol, and 90%±2%Cyclobenzaprine HCl and 10%±2% mannitol.5. The pharmaceutical composition of embodiment 4, comprising 75%±2%Cyclobenzaprine HCl and 25%±2% mannitol.6. The pharmaceutical composition of any one of embodiments 1-5, whereinthe Cyclobenzaprine HCl:mannitol molar ratio is 1.76±0.1.7. The pharmaceutical composition of any one of embodiments 1-6, whereinthe Cyclobenzaprine HCl is micronized Cyclobenzaprine HCl.8. The pharmaceutical composition of any one of embodiments 1-7, furthercomprising a basifying agent.9. The pharmaceutical composition of embodiment 8, wherein the basifyingagent is K₂HPO₄.10. The pharmaceutical composition of embodiment 8, wherein thebasifying agent is Na₂HPO₄.11. The pharmaceutical composition of embodiment 8, wherein thebasifying agent is trisodium citrate, anhydrous.12. A method of manufacturing a eutectic composition of any one ofembodiments 1-11, comprising mixing Cyclobenzaprine HCl and mannitol ormilling Cyclobenzaprine HCl and mannitol.13. The method of embodiment 12, comprising milling Cyclobenzaprine HCland mannitol.14. The method of embodiment 13, wherein, the Cyclobenzaprine HCl andmannitol are milled in a high shear granulator.15. The method of embodiment 12, comprising mixing Cyclobenzaprine HCland mannitol.16. The method of embodiment 15, wherein the Cyclobenzaprine HCl andmannitol are mixed via compression.17. The method of embodiment 16, wherein the Cyclobenzaprine HCl andmannitol are compressed via roller compaction.18. The method of any one of embodiments 12-17, wherein theCyclobenzaprine HCl is micronized Cyclobenzaprine HCl.19. The method of any one of embodiments 12-18, wherein thepharmaceutical composition comprises a basifying agent.20. The method of embodiment 19, wherein the basifying agent is K₂HPO₄.21. The method of embodiment 19, wherein the basifying agent is Na₂HPO₄.22. The method of embodiment 19, wherein the basifying agent istrisodium citrate, anhydrous.23. A pharmaceutical composition comprising a eutectic of mannitol andAmitriptyline HCl.24. The pharmaceutical composition of embodiment 23, wherein theeutectic mixture melts at 133±3° C.25. The pharmaceutical composition of embodiment 23, comprising 60%-90%Amitriptyline HCl and 40%-10% mannitol.26. The pharmaceutical composition of embodiment 25, comprising amountsof Amitriptyline HCl and mannitol selected from: 40%±2% AmitriptylineHCl and 60%±2% mannitol, 45%±2% Amitriptyline HCl and 55%±2% mannitol,50%±2% Amitriptyline HCl and 50%±2% mannitol, 55%±2% Amitriptyline HCland 45%±2% mannitol, 60%±2% Amitriptyline HCl and 40%±2% mannitol,65%±2% Amitriptyline HCl and 35%±2% mannitol, 70%±2% Amitriptyline HCland 30%±2% mannitol, 75%±2% Amitriptyline HCl and 25%±2% mannitol,80%±2% Amitriptyline HCl and 20%±2% mannitol, 85%±2% Amitriptyline HCland 15%±2% mannitol, and 90%±2% Amitriptyline HCl and 10%±2% mannitol.27. The pharmaceutical composition of embodiment 26, comprising 75%±2%Amitriptyline HCl and 25%±2% mannitol.28. The pharmaceutical composition of embodiment 26, comprising 50%±2%Amitriptyline HCl and 50%±2% mannitol.29. The pharmaceutical composition of any one of embodiments 23-28,wherein the Amitriptyline HCl is micronized Amitriptyline HCl.30. The pharmaceutical composition of any one of embodiments 23-29,further comprising a basifying agent.31. The pharmaceutical composition of embodiment 30, wherein thebasifying agent is K₂HPO₄.32. The pharmaceutical composition of embodiment 30, wherein thebasifying agent is Na₂HPO₄.33. The pharmaceutical composition of embodiment 30, wherein thebasifying agent is trisodium citrate, anhydrous.34. A method of manufacturing a eutectic composition of any one ofembodiments 23-33, comprising mixing Amitriptyline HCl and mannitol ormilling Amitriptyline HCl and mannitol.35. The method of embodiment 34, comprising milling Amitriptyline HCland mannitol.36. The method of embodiment 35, wherein, the Amitriptyline HCl andmannitol are milled in a high shear granulator.37. The method of embodiment 34, comprising mixing Amitriptyline HCl andmannitol.38. The method of embodiment 37, wherein the Amitriptyline HCl andmannitol are mixed via compression.39. The method of embodiment 38, wherein the Amitriptyline HCl andmannitol are compressed via roller compaction.40. The method of any one of embodiments 34-39, wherein theAmitriptyline HCl is micronized Amitriptyline HCl.41. The method of any one of embodiments 34-40, wherein thepharmaceutical composition comprises a basifying agent.42. The method of embodiment 41, wherein the basifying agent is K₂HPO₄.43. The method of embodiment 41, wherein the basifying agent is Na₂HPO₄.44. The method of embodiment 41, wherein the basifying agent istrisodium citrate, anhydrous.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: DSC heating curve of Cyclobenzaprine HCl.

FIG. 2: DSC heating curve of Cyclobenzaprine HCl+Sodium stearyl Fumarate1:1.

FIG. 3: DSC heating curve of Cyclobenzaprine HCl+Sodium stearylFumarate, formulation ratio.

FIG. 4: DSC heating curve of Cyclobenzaprine HCl+Potassium Phosphatedibasic 1:1.

FIG. 5: DSC heating curve of Cyclobenzaprine HCl+Potassium Phosphatedibasic, formulation ratio.

FIG. 6: DSC heating curve of Cyclobenzaprine HCl+Crospovidone (KollidonCL) 1:1.

FIG. 7: DSC heating curve of Cyclobenzaprine HCl+Silicon (colloidal)1:1.

FIG. 8: DSC heating curve of Cyclobenzaprine HCl+Pearlitol Flash® 1:1.

FIG. 9: DSC heating curve of Cyclobenzaprine HCl+Pearlitol Flash®,formulation ratio.

FIG. 10: DSC heating curve of Cyclobenzaprine HCl+Opadry Clear 1:1.

FIG. 11: DSC heating curve of Cyclobenzaprine HCl+Opadry II Clear 1:1.

FIG. 12: DSC heating curve relative to final, formulation mixture.

FIG. 13: DSC heating curve relative to the tablet at time zero ofCyclobenzaprine HCl.

FIG. 14: DSC heating curve relative to the tablet of Cyclobenzaprine HClat 40° C.

FIG. 15: DSC heating curve relative to tablet Cyclobenzaprine HCl afterstorage at 50° C.

FIG. 16: DSC heating curve of Cyclobenzaprine HCl.

FIG. 17: DSC heating curve of Cyclobenzaprine HCl+Sodium phosphateanhydrous 1:1 (mixture A).

FIG. 18: DSC heating curve of Cyclobenzaprine HCl+Sodium phosphateanhydrous 1:1 (mixture B).

FIG. 19: Comparison of DSC heating curves of Cyclobenzaprine HCl+Sodiumphosphate anhydrous 1:1 (mixture A & B).

FIG. 20: DSC heating curve of Cyclobenzaprine HCl+Sodium phosphatedihydrate 1:1 (mixture A).

FIG. 21: DSC heating curve of Cyclobenzaprine HCl+Sodium phosphatedihydrate 1:1 (mixture B).

FIG. 22: Comparison of DSC heating curves of Cyclobenzaprine HCl+Sodiumphosphate dihydrate 1:1 (mixture A & B).

FIG. 23: DSC heating curve of Cyclobenzaprine HCl+Sodium phosphateheptahydrate 1:1 (mixture A).

FIG. 24: DSC heating curve of Cyclobenzaprine HCl+Sodium phosphateheptahydrate 1:1 (mixture B).

FIG. 25: Comparison of DSC heating curves of Cyclobenzaprine HCl+Sodiumphosphate heptahydrate 1:1 (mixture A & B).

FIG. 26: DSC heating curve of Cyclobenzaprine HCl+Sodium citratedihydrate 1:1 (mixture A).

FIG. 27: DSC heating curve of Cyclobenzaprine HCl+Sodium citratedihydrate 1:1 (mixture B).

FIG. 28: Comparison of DSC heating curves of Cyclobenzaprine HCl+Sodiumcitrate dihydrate 1:1 (mixture A & B).

FIG. 29: DSC heating curve of Cyclobenzaprine HCl+Effersoda® Effersoda®®1:1 (mixture A).

FIG. 30: DSC heating curve of Cyclobenzaprine HCl+Effersoda® Effersoda®®1:1 (mixture B).

FIG. 31: Comparison of DSC heating curves of CyclobenzaprineHCl+Effersoda® 1:1 (mixture A & B).

FIG. 32: DSC heating curve of Cyclobenzaprine HCl+Sorbitol 1:1 (mixtureA).

FIG. 33: DSC heating curve of Cyclobenzaprine HCl+Sorbitol 1:1 (mixtureB).

FIG. 34: Comparison of DSC heating curves of CyclobenzaprineHCl+Sorbitol 1:1 (mixture A & B).

FIG. 35: Stacking of XRPD patterns of Cyclobenzaprine HCl+Sorbitol 1:1(mixture B).

FIG. 36: DSC heating curve of Cyclobenzaprine HCl+Mannitol 1:1 (mixtureA).

FIG. 37: DSC heating curve of Cyclobenzaprine HCl+Mannitol 1:1 (mixtureB).

FIG. 38: Comparison of DSC heating curves of CyclobenzaprineHCl+Mannitol 1:1 (mixture A & B).

FIG. 39: DSC heating curve of Cyclobenzaprine HCl+Trisodium citrateanhydrous 1:1 (mixture A).

FIG. 40: DSC heating curve of Cyclobenzaprine HCl+Trisodium citrateanhydrous 1:1 (mixture A).

FIG. 41: Comparison of DSC heating curves of CyclobenzaprineHCl+Trisodium citrate anhydrous 1:1 (mixture A & B).

FIG. 42: DSC heating curve of Cyclobenzaprine HCl+Disodium glycinecarbonate 1:1 (mixture A).

FIG. 43: DSC heating curve of Cyclobenzaprine HCl+Disodium glycinecarbonate 1:1 (mixture B).

FIG. 44: Comparison of DSC heating curve of Cyclobenzaprine HCl+Disodiumglycine carbonate 1:1 (mixture A & B).

FIG. 45: FT-IR/ATR spectra stacking of Cyclobenzaprine HCl+Trisodiumcitrate anhydrous 1:1 (mixture A).

FIG. 46: FT-IR/ATR spectra stacking of Cyclobenzaprine HCl+Trisodiumcitrate anhydrous 1:1 (mixture A).

FIG. 47: FT-IR/ATR spectra stacking of Cyclobenzaprine HCl+Trisodiumcitrate anhydrous 1:1 (mixture A).

FIG. 48: FT-IR/ATR spectra stacking of Cyclobenzaprine HCl+Trisodiumcitrate anhydrous 1:1 (mixture A & B).

FIG. 49: FT-IR/ATR spectra stacking of Cyclobenzaprine HCl+DisodiumGlycine carbonate 1:1 (mixture A).

FIG. 50: FT-IR/ATR spectra stacking of Cyclobenzaprine HCl+DisodiumGlycine carbonate 1:1 (mixture A).

FIG. 51: FT-IR/ATR spectra stacking of Cyclobenzaprine HCl+DisodiumGlycine carbonate 1:1 (mixture A).

FIG. 52: FT-IR/ATR spectra stacking of Cyclobenzaprine HCl+DisodiumGlycine carbonate 1:1 (mixture A & B).

FIG. 53: DSC heating curve of Cyclobenzaprine HCl.

FIG. 54: DSC heating curve of Mannitol, beta form.

FIG. 55: DSC heating curve of a mixture of Cyclobenzaprine HCl andMannitol at 15% of API.

FIG. 56: DSC heating curve of a mixture of Cyclobenzaprine HCl andMannitol at 30% of API.

FIG. 57: DSC heating curve of a mixture of Cyclobenzaprine HCl andMannitol at 40% of API.44

FIG. 58: DSC heating curve of a mixture of Cyclobenzaprine HCl andMannitol at 45% of API.

FIG. 59: DSC heating curve of a mixture of Cyclobenzaprine HCl andMannitol at 50% of API.

FIG. 60: DSC heating curve of a mixture of Cyclobenzaprine HCl andMannitol at 65% of API.

FIG. 61: DSC heating curve of a mixture of Cyclobenzaprine HCl andMannitol at 75% of API.

FIG. 62: DSC heating curve of a mixture of Cyclobenzaprine HCl andMannitol at 80% of API.

FIG. 63: DSC heating curve of a mixture of Cyclobenzaprine HCl andMannitol at 90% of API.

FIG. 64: DSC heating curve of a mixture of Cyclobenzaprine HCl andMannitol at 95% of API.

FIG. 65: Phase diagram of binary mixtures between Cyclobenzaprine HCland Mannitol.

FIG. 66: Plot of melting enthalpy as function of API percentage.

FIG. 67: XRPD pattern of Cyclobenzaprine HCl.

FIG. 68: XRPD peaks of Cyclobenzaprine HCl (table).

FIG. 69: XRPD pattern of Mannitol, beta form.

FIG. 70: XRPD peaks of Mannitol, beta form (table).

FIG. 71: Stacking of XRPD patterns of pure compounds and eutecticmixture.

FIG. 72: Stacking of XRPD patterns of pure compounds and mixtures.

FIG. 73: Linearity of Mannitol peaks in the range of 14.1-15° 2θ.

FIG. 74: Linearity of API peaks in the range of 12.5-13.3° 2θ.

FIG. 75: DSC heating curve of Amitriptyline HCl.

FIG. 76: DSC heating curve of Amitriptyline HCl+Sodium stearyl Fumarate1:1.

FIG. 77: DSC heating curve of Amitriptyline HCl+Stearic acid 1:1.

FIG. 78: DSC heating curve of Amitriptyline HCl+Glycerol dibehenate 1:1.

FIG. 79: DSC heating curve of Amitriptyline HCl+Magnesium stearate 1:1.

FIG. 80: DSC heating curve of Amitriptyline HCl+Pearlitol flash 1:1.

FIG. 81: Eutectic evaluation of DSC heating curve of API+Pearlitol 1:1.

FIG. 82: DSC heating curve of Amitriptyline HCl+Pearlitol 200SD/Mannitol 1:1.

FIG. 83: Eutectic evaluation of DSC heating curve ofAPI+Pearlitol/mannitol 1:1.

FIG. 84: DSC heating curve of Amitriptyline HCl+Unipure DW/Corn starchpartially pregelatinized 1:1.

FIG. 85: DSC heating curve of Amitriptyline HCl+Crospovidone—Kollidon CL1:1.

FIG. 86: DSC heating curve of Amitriptyline HCl+SiliconColloidal/Aerosil 200 1:1.

FIG. 87: DSC heating curve of Amitriptyline HCl+Sodium phosphate dibasic1:1.

FIG. 88: DSC heating curve of Amitriptyline HCl+Sodium bicarbonate 1:1.

FIG. 89: DSC heating curve of Amitriptyline HCl+Sodium carbonate 1:1.

FIG. 90: DSC heating curve of Amitriptyline HCl+Sodium phosphatedodecahydrate 1:1.

FIG. 91: DSC heating curve of Amitriptyline HCl+Sodium phosphateanhydrous 1:1.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined herein, scientific and technical terms used inthis application shall have the meanings that are commonly understood bythose of ordinary skill in the art. Generally, nomenclature used inconnection with, and techniques of, pharmacology, cell and tissueculture, molecular biology, cell and cancer biology, neurobiology,neurochemistry, virology, immunology, microbiology, genetics and proteinand nucleic acid chemistry, described herein, are those well known andcommonly used in the art.

The methods and techniques of the present invention are generallyperformed, unless otherwise indicated, according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout thisspecification.

Chemistry terms used herein are used according to conventional usage inthe art, as exemplified by “The McGraw-Hill Dictionary of ChemicalTerms”, Parker S., Ed., McGraw-Hill, San Francisco, Calif. (1985).

All of the above, and any other publications, patents and publishedpatent applications referred to in this application are specificallyincorporated by reference herein. In case of conflict, the presentspecification, including its specific definitions, will control.

Throughout this specification, the word “comprise” or variations such as“comprises” or “comprising” will be understood to imply the inclusion ofa stated integer (or components) or group of integers (or components),but not the exclusion of any other integer (or components) or group ofintegers (or components).

The singular forms “a,” “an,” and “the” include the plurals unless thecontext clearly dictates otherwise.

The term “including” is used to mean “including but not limited to.”“Including” and “including but not limited to” are used interchangeably.

A “patient”, “subject”, or “individual” are used interchangeably andrefer to either a human or a non-human animal. These terms includemammals, such as humans, primates, livestock animals (including bovines,porcines, etc.), companion animals (e.g., canines, felines, etc.) androdents (e.g., mice and rats).

“Treating” a condition or patient refers to taking steps to obtainbeneficial or desired results, including clinical results. Beneficial ordesired clinical results include, but are not limited to, alleviation oramelioration of one or more symptoms associated with a disease orcondition as described herein.

“Administering” or “administration of” a substance, a compound or anagent to a subject can be carried out using one of a variety of methodsknown to those skilled in the art. For example, a compound or an agentcan be administered sublingually or intranasally, by inhalation into thelung or rectally. Administering can also be performed, for example,once, a plurality of times, and/or over one or more extended periods. Insome aspects, the administration includes both direct administration,including self-administration, and indirect administration, includingthe act of prescribing a drug. For example, as used herein, a physicianwho instructs a patient to self-administer a drug, or to have the drugadministered by another and/or who provides a patient with aprescription for a drug is administering the drug to the patient.

In solid drug product formulation, the knowledge of possibleinteractions between the drug substance and the excipients is a crucialpoint for the prediction of chemical and physical stability.

Very often the excipients can modify the biological activity andchemical stability of the API because the dissolution or chemicalstructures are changed. In some cases, the excipient can improve thechemical stability profile over time and avoid undesirable physicalbehavior of the final dosage form.

A eutectic system is a mixture of chemical compounds or elements thathas a single chemical composition that melts at a lower temperature thanany other composition made up of the same ingredients. A compositioncomprising a eutectic is known as the eutectic composition and itsmelting temperature is known as the eutectic temperature. To define aeutectic composition, a binary phase diagram should be built byanalyzing different compounds ratios.

The effect of a eutectic on tablet properties shows that compactionprovides the intimate contact and mutual solubility sufficient foreutectic formation. Eutectic compositions often have higher stabilityand/or dissolution rates than their non-eutectic counterparts. Becauseeutectics enhance dissolution, they can be employed to increasepermeability in solid dispersions and dispersion systems. However, inthe development of certain tableted dosage forms, undesired eutecticformation (during manufacturing operation such as wet granulation), canlead to unwanted changes in physical or chemical characteristics of thetablet, such as low eutectic melting temperature, sticking,unpredictable hardness, instability or difficulties in acceleratedassessment of stability.

Mannitol and Sorbitol are excipients commonly used in solid drugproducts. Mannitol and Sorbitol are 6-carbon sugar alcohols isomers.Sugar alcohols are hydrogenated carbohydrates whose carbonyl group hasbeen reduced to a primary or secondary hydroxyl group. Other 6-carbonsugar alcohols include Inositol, Galactitol, Fucitol, and Iditol.

Although Mannitol and Sorbitol can be included in pharmaceuticalcompositions, it is typically because they provide qualitative benefitssuch as sweet taste or a cooling effect in the mouth, but are physicallyinert. Thus, it was surprising to discover that mannitol formed aeutectic composition with Cyclobenzaprine HCl and with AmitriptylineHCl. By contrast, sorbitol dissolved Cyclobenzaprine HCl and did notform a eutectic, underscoring the unpredictability of eutecticformation. Without wishing to be bound by theory, it is possible thatthe two co-penetrating crystal lattices of mannitol and CyclobenzaprineHCl provide protection of the Cyclobenzaprine HCl from hydration andother chemical interactions.

Compounds

The compounds useful in embodiments of the present invention includeCyclobenzaprine HCl and Amitriptyline HCl. In some embodiments, thecompounds are micronized. In alternative embodiments, the compounds arenot micronized. In some embodiments, the compounds may be present in oneor more crystal isoforms.

As used herein, “Cyclobenzaprine HCl” refers to the pharmaceuticallyacceptable Cyclobenzaprine hydrochloride salt of cyclobenzaprine.

As used herein, “Amitriptyline HCl” refers to the pharmaceuticallyacceptable Amitriptyline hydrochloride salt of amitriptyline.

Eutectic Compositions

In some embodiments, the invention provides a pharmaceutical compositioncomprising a eutectic mixture of mannitol and an active pharmaceuticalingredient. In certain embodiments, the active pharmaceutical ingredientis Cyclobenzaprine HCl or Amitriptyline HCl.

In some embodiments, the invention provides a pharmaceutical compositioncomprising a eutectic mixture of mannitol and Cyclobenzaprine HCl. Incertain embodiments, the composition has a melting temperature of143.6±3° C. In certain embodiments, a melting temperature of thecomposition is approximately 135.6° C., 136.6° C., 137.6° C., 138.6° C.,139.6° C., 140.6° C., 141.6° C., 142.6° C., 143.6° C., 144.6° C., 145.6°C., 146.6° C., 147.6° C., 148.6° C., 149.6° C., 150.6° C., 151.6° C.,152.6° C., or 153.6° C. In certain embodiments, the compositioncomprises 10%-90% Cyclobenzaprine HCl and 90%-10% mannitol by weight,for example, 60%-90% Cyclobenzaprine HCl and 40%-10% mannitol or 70%-80%Cyclobenzaprine HCl and 30%-20% mannitol by weight. Exemplarycompositions comprise 60%±2% Cyclobenzaprine HCl and 40%±2% mannitol,65%±2% Cyclobenzaprine HCl and 35%±2% mannitol, 70%±2% CyclobenzaprineHCl and 30%±2% mannitol, 75%±2% Cyclobenzaprine HCl and 25%±2% mannitol,80%±2% Cyclobenzaprine HCl and 20%±2% mannitol, 85%±2% CyclobenzaprineHCl and 15%±2% mannitol, and 90%±2% Cyclobenzaprine HCl and 10%±2%mannitol by weight. In certain embodiments, a composition comprises75%±10% Cyclobenzaprine HCl and 25%±10% mannitol by weight. In certainembodiments, a composition comprises 75%±2% Cyclobenzaprine HCl and25%±2% mannitol by weight. In certain embodiments, a compositioncomprises 75% Cyclobenzaprine HCl and 25% mannitol by weight. In certainembodiments, the composition comprises Cyclobenzaprine HCl and mannitolin a Cyclobenzaprine HCl:mannitol molar ratio of 1.70±0.1 to 1.80±0.1.In certain embodiments, the molar ratio is 1.70±0.1, 1.71±0.1, 1.72±0.1,1.73±0.1, 1.74±0.1, 1.75±0.1, 1.76±0.1, 1.77±0.1, 1.78±0.1, 1.79±0.1, or1.80±0.1. In certain embodiments the molar ratio is 1.76±0.1.

In some embodiments, the invention provides a pharmaceutical compositioncomprising a eutectic mixture of mannitol and Amitriptyline HCl. Incertain embodiments, the composition has a melting temperature of 133±3°C. In certain embodiments, a melting temperature of the composition isapproximately 125° C., 126° C., 127° C., 128° C., 129° C., 130° C., 131°C., 132° C., 133° C., 134° C., 135° C., 136° C., 137° C., 138° C., 139°C., 140° C., 141° C., 142° C., or 143° C. In certain embodiments, thecomposition comprises 10%-90% Amitriptyline HCl and 90%-10% mannitol byweight, for example, 60%-90% Amitriptyline HCl and 40%-10% mannitol or70%-80% Amitriptyline HCl and 30%-20% mannitol by weight. Exemplarycompositions comprise 60%±2% Amitriptyline HCl and 40%±2% mannitol,65%±2% Amitriptyline HCl and 35%±2% mannitol, 70%±2% Amitriptyline HCland 30%±2% mannitol, 75%±2% Amitriptyline HCl and 25%±2% mannitol,80%±2% Amitriptyline HCl and 20%±2% mannitol, 85%±2% Amitriptyline HCland 15%±2% mannitol, and 90%±2% Amitriptyline HCl and 10%±2% mannitol byweight. In certain embodiments, a composition comprises 75%±10%Amitriptyline HCl and 25%±10% mannitol by weight. In certainembodiments, a composition comprises 75%±2% Amitriptyline HCl and 25%±2%mannitol by weight. In certain embodiments, a composition comprises 75%Amitriptyline HCl and 25% mannitol by weight. In certain embodiments,the composition comprises Amitriptyline HCl and mannitol in aAmitriptyline HCl:mannitol molar ratio 1.70±0.1 to 1.80±0.1. In certainembodiments, the molar ratio is of 1.70±0.1, 1.71±0.1, 1.72±0.1,1.73±0.1, 1.74±0.1, 1.75±0.1, 1.76±0.1, 1.77±0.1, 1.78±0.1, 1.79±0.1, or1.80±0.1. In certain embodiments the molar ratio is 1.76±0.1.

Another benefit of the eutectic compositions of the invention isincreased stability of a tablet containing Cyclobenzaprine HCl. In someembodiments, the invention provides a pharmaceutical compositioncomprising Cyclobenzaprine HCl and mannitol or Amitriptyline HCl andmannitol, wherein the composition has an increased stability in tabletform as compared to the same tablet without mannitol, e.g., to a tabletcomprising sorbitol but not mannitol. Indeed, a tablet containingCyclobenzaprine HCl, K₂HPO₄, and mannitol was stable for three months at40° C. and 75% relative humidity. By contrast, a tablet containingCyclobenzaprine HCl, K₂HPO₄, and sorbitol stored at the same conditionsdisintegrated before reaching even reaching one week.

In some embodiments, the invention provides a pharmaceutical compositioncomprising Cyclobenzaprine HCl and mannitol or Amitriptyline HCl andmannitol, wherein the composition has an increased dissolution rate of astable tablet compared to Cyclobenzaprine HCl or Amitriptyline HCl aloneor in a formulation containing one or more excipients that are notbasifying agents. For example, the composition at 5 minutes can exhibitgreater than 55%, greater than 50%, greater than 45%, greater than 40%,greater than 35%, greater than 30%, or greater than 25% dissolution whenmixed with 100 mL of 50 mM Citrate pH 4 at 37.0±0.5° C. For example, thecomposition at 10 minutes can exhibit greater than 80%, greater than75%, greater than 65%, greater than 60%, greater than 55%, greater than50%, dissolution when mixed with 100 mL of 50 mM Citrate pH 4 at37.0±0.5° C. For example, the composition at 240 minutes can exhibitgreater than 80%, greater than 75%, greater than 65%, greater than 60%,greater than 55%, greater than 50%, dissolution when mixed with 100 mLof 50 mM Citrate pH 4 at 37.0±0.5° C.

Methods of Manufacturing Eutectic Compositions

The skilled worker will appreciate that a eutectic composition of theinvention can be manufactured according to any of a number of knownmethods. In some embodiments, the invention provides methods forproducing a eutectic composition of the invention comprising milling anAPI (Cyclobenzaprine HCl or Amitriptyline HCl) with mannitol, mixing anAPI (Cyclobenzaprine HCl or Amitriptyline HCl) with mannitol, or acombination thereof. For example, the API and mannitol can be milled inan agate mortar or mixed in a high shear granulator. High shear mixingcombines dry powders using a high speed impellor and chopper blades touniformly mix the ingredients. Some particle size reduction is possibledue to the shear force and the high speed of the mixing blades. The APIand mannitol also can be milled and mixed in a Turbula® Shaker-Mixer. Incertain embodiments, the API and mannitol can be mixed via compression,for example, via roller compaction. Roller compaction forces finepowders between two counter-rotating rolls and presses the raw materialsinto a solid compact or sheet (referred to as flakes). The flakes arereduced in size until they reach a desired grain size. In certainembodiments, mannitol can be melted and mixed with Cyclobenzaprine HClor Amitriptyline HCl to form a eutectic composition. In certainembodiments, the API is a micronized API (e.g., micronizedCyclobenzaprine HCl or micronized Amitriptyline HCl).

Methods of Detecting Eutectic Compositions

Methods of detecting eutectic compositions are well known. The skilledworker will appreciate that eutectic compositions can be detected by anyof these methods. For example, rapid differential scanning calorimetry(“DSC”) can be used to detect a eutectic melting point by evaluating theamount of heat recorded from eutectic melting and comparing it with themelting heat of the eutectic composition. During a slow scan of DSC, theincreased temperature in the crucible facilitates the formation of theeutectic even when the two components (such as Mannitol andcyclobenzaprine HCl may not have been mixed before the start of theexperiment.) In contrast, a rapid DSC scan reduces the time during whicheutectic compositions can form in the crucible because the temperatureinside the crucible rapidly increases during the analysis and rapidlyreaches the values at which the mannitol melts. Another useful method ismeasuring compaction force vs. DSC eutectic melting point. In thismethod, mixtures are prepared with known ratios and then submitted towell defined compaction forces. DSC analyses are then performed and theheat of the eutectic melting versus the forces is then recorded andplotted. These values are compared with those obtained with the eutecticratio, providing the percentage of eutectic in the formulation.

An additional method that can be used to detect the amount of eutecticin a composition is to compare tensile strength and compression force.In this method, tablets are prepared with only mannitol and API atdifferent compression forces. For each tablet prepared, the percentageof eutectic formed versus tensile strength of the tablets is correlated.There is a proportionally linear correlation between the tensilestrength and the intimate contact area. The slope of this correlationprovides the percentage of the eutectic formed.

There is a linear correlation between the percentage of eutecticcomposition in a preparation and the porosity of powders in acomposition. In this method, a standard curve can be generated bypreparing samples with different ratios of components in which at leastone of the components has a variety of different particle sizes,measuring the specific surface area and the porosity of the powders andplotting porosity against the percentage of eutectic. Because there is alinear correlation between the two parameters, the slope of thiscorrelation with what is recorded for the eutectic mixture provides thepercentage of the eutectic formed

Dissolution rate also can be used to detect the percent of eutecticbecause a eutectic may have higher dissolution and higherbioavailability. In this method, the intrinsic dissolution rate (usingdisk sample holder in a defined and appropriate medium) of the singlecomponents is calculated, followed by the dissolution rate of theeutectic mixture. Based on the thermodynamic parameters (entropy), theeutectic should have a more rapid dissolution rate than the othermixtures. By these analyses, it is also possible to obtain informationon the performance of a tablet in terms of bioavailability. Thisapproach also can evaluate the higher bioavailability of a eutecticversus mixtures of the individual components.

Scanning Electron Microscopy (SEM) can be used by performing a scanningEM of each pure component, on the eutectic, and on the mixtures, andobserving the different crystal morphology by pointing out thedifferently shaped particles.

Methods of Administering Eutectic Compositions

Appropriate methods of administering a pharmaceutical composition of theinvention to a subject will depend, for example, on the age of thesubject, whether the subject is active or inactive at the time ofadministering, whether the subject is experiencing symptoms of a diseaseor condition at the time of administering, the extent of the symptoms,and the chemical and biological properties of the API (e.g. solubility,digestibility, bioavailability, stability and toxicity). In someembodiments, the pharmaceutical composition is administered for oral ortransmucosal absorption.

Methods of administering compositions for oral absorption are well knownin the art. For example, a composition may be administered for oralabsorption through tablets, capsules, pills, or powders.

Methods of administering compositions for transmucosal absorption arewell known in the art. For example, a composition may be administeredfor buccal absorption through buccal tablets, lozenges, buccal powders,and buccal spray solutions. A composition may be administered forsublingual absorption through sublingual tablets, sublingual films,liquids, sublingual powders, and sublingual spray solutions. Acomposition may be administered for intranasal absorption through nasalsprays. A composition may be administered for pulmonary absorptionthrough aerosolized compositions and inhalable dried powders. Whenadministered via sprays or aerosolized compositions, a composition maybe prepared with saline as a solution, employ benzyl alcohol or othersuitable preservatives, or include absorption promoters to enhancebioavailability, fluorocarbons, and/or other solubilizing or dispersingagents.

Doses and dosing regimens can be determined by one of skill in the artaccording to the needs of a subject to be treated. The skilled workermay take into consideration factors such as the age or weight of thesubject, the severity of the disease or condition being treated, and theresponse of the subject to treatment. A composition of the invention canbe administered, for example, as needed or on a daily basis. In someembodiments, a composition can be administered immediately prior tosleep or several hours before sleep. Administration prior to sleep maybe beneficial by providing the therapeutic effect before the onset ofthe symptoms of the disease or condition being treated. Dosing may takeplace over varying time periods. For example, a dosing regimen may lastfor 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or longer. In someembodiments, a dosing regimen will last 1 month, 2 months, 3 months, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or longer.

Therapeutic Uses

The pharmaceutical compositions of the invention may be employed fortreating or preventing the development of fibromyalgia syndrome, alsoknown as fibrositis (see, e.g., Moldofsky et al. J Rheumatol38(12):2653-2663 (2011) and Thomas, J Rheumatol 38(12):2499-2500(2011)). Fibromyalgia is a chronic, non-inflammatory rheumatic disorder.The American College of Rheumatology (ACR) published classificationcriteria for fibromyalgia in 1990 (Wolfe, F., et al., Arthritis andRheumatism 33:160-172 (1990)). Subsequently, a modification to the ACRcriteria been published (Wolfe et al., J Rheumatol 38(6):1113-22(2011)). Diagnostic criteria have also been published by aninternational network of working groups called, “Outcome Measures inRheumatology” clinical trials or OMERACT (Mease P, et al. J Rheumatol.2009; 36(10):2318-29.). Fibromyalgia is traditionally characterized bystiffness or diffuse pain, aches, muscle soreness, sleep disturbances orfatigue. The pain is generally widespread and generally localized atspecific “tender points,” which may bring on widespread pain and musclespasm when touched. Other symptoms include mental and emotionaldisturbances such as poor concentration and irritability,neuropsychiatric symptoms such as depression and anxiety, jointswelling, headache, numbness. Fibromyalgia is associated withnonrefreshing sleep, tiredness, sleepiness, reflux, mental fog andcognitive impairments including difficulty multi-tasking. Fibromyalgiaalso is often comorbid with sleep disorders, fatigue, non-restorativesleep, anxiety, and depression. The compositions and methods of theinvention can be used to treat any one of the above-identifiedconditions, and any combination thereof.

Some practitioners further classify fibromyalgia into twocategories—primary or secondary-concomitant fibromyalgia. Generally,primary fibromyalgia syndrome can be considered fibromyalgia occurringin the absence of another significant condition whereassecondary-concomitant fibromyalgia can be considered fibromyalgiaoccurring in the presence of another significant medical disorder, whichmay have been caused by or is merely associated with the patient'sfibromyalgia. Secondary or concomitant fibromyalgia can includefibromyalgia in patients with classical or definite rheumatoidarthritis, osteoarthritis of the knee or hand, low back pain syndromes,cervical pain syndromes, cancer pain syndromes, temporomandibular jointdisorders, migraine headaches, menopause, post-traumatic stress disorderand interstitial cystitis or painful bladder syndrome (or combinationsthereof).

The compositions of the invention also may be employed for treating orpreventing the development (either the initiation, consolidation orperpetuation) of a PTSD symptom following a traumatic event. A traumaticevent is defined as a direct personal experience that involves actual orthreatened death or serious injury, or other threat to one's physicalintegrity, or witnessing an event that involves death, injury, or athreat to the physical integrity of another person; or learning aboutunexpected or violent death, serious harm, or threat of death or injuryexperienced by a family member or other close associate. Traumaticevents that are experienced directly include, but are not limited to,military combat, violent personal assault (sexual assault, physicalattack, robbery, mugging), being kidnapped, being taken hostage,terrorist attack, torture, incarceration as a prisoner of war or in aconcentration camp, natural or manmade disasters, severe automobileaccidents, or being diagnosed with a life-threatening illness. Forchildren, sexually traumatic events may include developmentallyinappropriate sexual experiences without threatened or actual violenceor injury. Witnessed events include, but are not limited to, observingthe serious injury or unnatural death of another person due to violentassault, accident, war, or disaster or unexpectedly witnessing a deadbody or body parts. Events experienced by others that are learned aboutmay include, but are not limited to, violent personal assault, seriousaccident, or serious injury experienced by a family member or a closefriend, learning about the sudden, unexpected death of a family memberor a close friend, or learning that one's child has a life-threateningdisease. The disorder may be especially severe or long lasting when thestressor is of human design (e.g., torture or rape). The initiation of aPTSD symptom typically occurs immediately following the traumatic event,during which the symptoms of PTSD appear and become increasingly severe.One theory of how PTSD develops is that there is a type of “learning” orreinforcement process during which the memories of the trauma areengrained in the mind. As these memories become more fixed (a processcalled consolidation), symptoms such as flashbacks and nightmares growin severity and frequency. Interventions during this critical time mayprevent some patients from developing full-blown PTSD. The consolidationof a PTSD symptom typically occurs during the weeks and months followinga traumatic event. A person's memories of that event become consolidatedinto highly vivid and concrete memories that are re-experienced withincreasing frequency either as flashbacks or nightmares. During thistime, hyperarousal symptoms and avoidant behavior can becomeincreasingly severe and disabling. The perpetuation of a PTSD symptomoccurs once traumatic memories are consolidated, and the re-experiencedsymptoms (flashbacks and nightmares) and hyperarousal symptoms becomepersistent and remain at a level that is functionally disabling to thepatient.

The compositions of the invention may be used to treat different phasesof PTSD development at various time intervals after a traumatic event.For example, treating the initiation phase of PTSD may require theadministration of a composition of the invention soon after thetraumatic event, for example within the first week, within the secondweek, within the third week, or within the fourth week or later. Bycontrast, when treating the consolidation phase of PTSD, the skilledworker may be able to administer a composition of the invention laterafter the traumatic event and later during the development of thesymptoms, for example, within the first month, within the second month,or within the third month or later. The perpetuation phase of PTSD maybe treated with a composition of the invention administered 3 months orlonger after the traumatic event, for example within the third month,within the fourth month, within the fifth month, or later. As a resultof treatment at the initiation, consolidation, or perpetuation phase,PTSD symptoms will be ameliorated or be eliminated.

The compositions of the invention also can be used to treat traumaticbrain injury (TBI). TBI is associated with sleep disorders, sleepdisturbances, fatigue, non-restorative sleep, anxiety, and depression.The compositions and methods of the invention also can be used to treatany of the above conditions, in combination with or independently oftreating TBI.

The compositions of the invention also can be used to chronic traumaticencephalopathy (CTE). CTE is associated with sleep disorders, sleepdisturbances, fatigue, non-restorative sleep, anxiety, and depression.The compositions and methods of the invention also can be used to treatany of the above conditions, in combination with or independently oftreating CTE.

The compositions and methods of the invention may be used to treat sleepdisorders or sleep disturbances. A “sleep disorder” may be any one offour major categories of sleep dysfunction (DSM-IV, pp. 551-607; seealso The International Classification of Sleep Disorders: (ICSD)Diagnostic and Coding Manual, 1990, American Sleep DisordersAssociation). One category, primary sleep disorders, comprises sleepdisorders that do not result from another mental disorder, a substance,or a general medical condition. They include without limitation primaryinsomnia, primary hypersomnia, narcolepsy, circadian rhythm sleepdisorder, nightmare disorder, sleep terror disorder, sleepwalkingdisorder, REM sleep behavior disorder, sleep paralysis, day/nightreversal and other related disorders; substance-induced sleep disorders;and sleep disorders due to a general medical condition. Primary insomnianon-restorative sleep is described by the DSM-IV-TR as a type of primaryinsomnia wherein the predominant problem is waking up feelingunrefreshed or nonrefreshed. A second category comprises those sleepdisorders attributable to substances, including medications and drugs ofabuse. A third category comprises sleep disturbances arising from theeffects of a general medical condition on the sleep/wake system. Afourth category of sleep disorders comprises those resulting from anidentifiable mental disorder such as a mood or anxiety disorder. A fifthcategory of sleep disorders comprises those described as non-restorativesleep. One definition of non-restorative sleep is in the DSM-IV-TR as atype of primary insomnia (A1.3) wherein the predominant problem iswaking up feeling unrefreshed or nonrefreshed. Symptoms of each categoryof sleep disorder are known in the art. A “sleep disturbance” may be animpairment in refreshing sleep. Such a clinical diagnosis may be madebased on a patient's self described feeling of fatigue upon waking orthe patient's report of poor quality sleep. Such impediments to goodquality sleep may be described as shallow sleep or frequent awakeningswhich may be associated with an increase in the Cyclic AlternatingPattern (CAP) A2 or A3 rate or cycle duration or an increase in thenormalized CAP A2+A3 which is determined by CAP (A2+A3)/CAP (A1+A2+A3)in non-REM sleep (see, e.g., Moldofsky et al. J Rheumatol38(12):2653-2663 (2011) and Thomas, J Rheumatol 38(12):2499-2500(2011)), alpha rhythm contamination in non-REM sleep, or absence ofdelta waves during deeper physically restorative sleep. Such “sleepdisturbances” may or may not rise to the level of a “sleep disorder” asdefined in the DSM-IV, although they may share one or more symptom incommon. Symptoms of sleep disturbances are known in the art. Among theknown symptoms are groggy or spacey feelings, tiredness, feelings ofbeing run down, and having difficulty concentrating during waking hours.Among the sleep-related conditions that may be treated with the methodsand compositions of the invention are dyssomnias (e.g., intrinsic sleepdisorders such as sleep state misperception, psychophysiologicalinsomnia, idiopathic insomnia, obstructive sleep apnea syndrome, centralsleep apnea syndrome, central alveolar hypoventilation syndrome,restless leg syndrome, and periodic limb movement disorder; extrinsicsleep disorders such as environmental sleep disorder, adjustment sleepdisorder, limit-setting sleep disorder, stimulant-dependent sleepdisorder, alcohol-dependent sleep disorder, toxin-induced sleepdisorder, sleep onset association disorder, hypnotic dependent sleepdisorder, inadequate sleep hygiene, altitude insomnia, insufficientsleep syndrome, nocturnal eating syndrome, and nocturnal drinkingsyndrome; and circadian rhythm sleep disorders such as jet lag syndrome,delayed sleep phase syndrome, advanced sleep phase syndrome, shift worksleep disorder, non-24 hour sleep-wake disorder, and irregularsleep-wake patterns), parasomnias (e.g., arousal disorders such assleepwalking, confusional arousals, and sleep terrors and sleep-waketransition disorders such as rhythmic movement disorder, sleep talkingand sleep starts, and nocturnal leg cramps), and sleep disordersassociated with medical or psychiatric conditions or disorders. Thecompositions of the invention also can be used to treat muscle spasms.Muscle spasms can be associated with muscle pain, e.g., back pain. Thecompositions and methods of the invention also can be used to treat anyof the above conditions, in combination with or independently oftreating muscle spasms.

Basifying Agents

The compositions of the invention may include a basifying agent. As usedherein, a “basifying agent” refers to an agent (e.g., a substance thatincreases the local pH of a liquid comprising Cyclobenzaprine HCl orAmitruptyline HCl, including potassium dihydrogen phosphate(monopotassium phosphate, monobasic potassium phosphate, KH₂PO₄),dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassiumphosphate, K₂HPO₄), tripotassium phosphate (K₃PO₄), sodium dihydrogenphosphate (monosodium phosphate, monobasic sodium phosphate, NaH₂PO₄),disodium hydrogen phosphate (disodium phosphate, dibasic sodiumphosphate, Na₂HPO₄), trisodium phosphate (Na₃PO₄), trisodium citrateanhydrous, bicarbonate or carbonate salts, borate, hydroxide, silicate,nitrate, dissolved ammonia, the conjugate bases of some organic acids(including bicarbonate), and sulfide) that raises the pH of a solutioncontaining Cyclobenzaprine HCl or Amitriptyline HCl. Without wishing tobe bound by theory, a basifying agent, while providing beneficialpharmacokinetic attributes to pharmaceutical compositions comprisingCyclobenzaprine HCl or Amitriptyline HCl, also may destabilize theCyclobenzaprine HCl or Amitriptyline HCl due to interactions between theHCl and basifying agent. Thus, a eutectic composition as describedherein may be especially useful in compositions comprising a basifyingagent.

Excipients

In some embodiments, a composition of the invention is useful as amedicament. In some embodiments, the invention provides for the use of acomposition of the invention in the manufacture of a medicament. In someembodiments, it may be beneficial to include one or more excipients inthe compositions of the invention. One of skill in the art wouldappreciate that the choice of any one excipient may influence the choiceof any other excipient. For example, the choice of a particularexcipient may preclude the use of one or more additional excipientbecause the combination of excipients would produce undesirable effects.One of skill in the art would be able to empirically determine whichadditional excipients, if any, to include in the formulations of theinvention. For example, Cyclobenzaprine HCl or Amitriptyline HCl can becombined with at least one pharmaceutically acceptable carrier such as asolvent, bulking agents, binder, humectant, disintegrating agent,solution retarder, disintegrant, glidant, absorption accelerator,wetting agent, solubilizing agent, lubricant, sweetening agent, orflavorant agent. A “pharmaceutically acceptable carrier” refers to anydiluent or excipient that is compatible with the other ingredients ofthe formulation, and which is not deleterious to the recipient. Apharmaceutically acceptable carrier can be selected on the basis of thedesired route of administration, in accordance with standardpharmaceutical practices.

Bulking Agents

In some embodiments, it may be beneficial to include a bulking agent inthe compositions of the invention. Bulking agents are commonly used inpharmaceutical compositions to provide added volume to the composition.Bulking agents are well known in the art. Accordingly, the bulkingagents described herein are not intended to constitute an exhaustivelist, but are provided merely as exemplary bulking agents that may beused in the compositions and methods of the invention.

Exemplary bulking agents may include carbohydrates, sugar alcohols,amino acids, and sugar acids. Bulking agents include, but are notlimited to, mono-, di-, or poly-, carbohydrates, starches, aldoses,ketoses, amino sugars, glyceraldehyde, arabinose, lyxose, pentose,ribose, xylose, galactose, glucose, hexose, idose, mannose, talose,heptose, glucose, fructose, methyl a-D-glucopyranoside, maltose,lactone, sorbose, erythrose, threose, arabinose, allose, altrose,gulose, idose, talose, erythrulose, ribulose, xylulose, psicose,tagatose, glucosamine, galactosamine, arabinans, fructans, fucans,galactans, galacturonans, glucans, mannans, xylans, inulin, levan,fucoidan, carrageenan, galactocarolose, pectins, amylose, pullulan,glycogen, amylopectin, cellulose, microcrystalline cellulose, pustulan,chitin, agarose, keratin, chondroitin, dermatan, hyaluronic acid,xanthin gum, sucrose, trehalose, dextran, lactose, alditols, inositols,sorbitol, mannitol, glycine, aldonic acids, uronic acids, aldaric acids,gluconic acid, isoascorbic acid, ascorbic acid, glucaric acid,glucuronic acid, gluconic acid, glucaric acid, galacturonic acid,mannuronic acid, neuraminic acid, pectic acids, maize starch, andalginic acid.

Disintegrants

In some embodiments, it may be beneficial to include a disintegrant inthe compositions of the invention. Disintegrants aid in the breakup ofsolid compositions, facilitating delivery of an active pharmaceuticalcomposition. Disintegrants are well known in the art. Some disintegrantshave been referred to as superdisintegrants because they have fastproperties, and may be used as disintegrants in the context of theinvention. Accordingly, the disintegrants described herein are notintended to constitute an exhaustive list, but are provided merely asexemplary disintegrants that may be used in the compositions and methodsof the invention. Exemplary disintegrants include crospovidone,microcrystalline cellulose, sodium carboxymethyl cellulose, methylcellulose, sodium starch glycolate, calcium carboxymethyl croscarmellosesodium, polyvinylpyrrolidone, lower alkyl-substituted hydroxypropylcellulose, Indion 414, starch, pre-gelatinized starch, calciumcarbonate, gums, sodium alginate, and Pearlitol Flash®. Pearlitol Flash®(Roquette) is a mannitol-maize starch disintegrant that is specificallydesigned for orally dispersible tablets (ODT). Certain disintegrantshave an efferverscent quality.

Glidants

In some embodiments, it may be beneficial to include a glidant in thecompositions of the invention. Glidants aid in the ability of a powderto flow freely. Glidants are well known in the art. Accordingly, theglidants described herein are not intended to constitute an exhaustivelist, but are provided merely as exemplary glidants that may be used inthe compositions and methods of the invention. Exemplary glidantsinclude colloidal silica (silicon dioxide), magnesium stearate, starch,talc, glycerol behenate, DL-leucine, sodium lauryl sulfate, calciumstearate, and sodium stearate.

Lubricants

In some embodiments, it may be beneficial to include a lubricant in thecompositions of the invention. Lubricants help keep the components of acomposition from clumping. Lubricants are well known in the art.Accordingly, the lubricants described herein are not intended toconstitute an exhaustive list, but are provided merely as exemplarylubricants that may be used in the compositions and methods of theinvention. Exemplary lubricants include calcium stearate, magnesiumstearate, stearic acid, sodium stearyl fumarate, vegetable based fattyacids, talc, mineral oil, light mineral oil, hydrogenated vegetable oil(e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil,corn oil, safflower oil, canola oil, coconut oil and soybean oil),silica, zinc stearate, ethyl oleate, ethyl laurate.

Sweeteners

In some embodiments, it may be beneficial to include a sweetener in thecompositions of the invention. Sweeteners help improve the palatabilityof the composition by conferring a sweet taste to the composition.Sweeteners are well known in the art. Accordingly, the sweetenersdescribed herein are not intended to constitute an exhaustive list, butare provided merely as exemplary sweeteners that may be used in thecompositions and methods of the invention. Exemplary sweeteners include,without limitation, compounds selected from the saccharide family suchas the mono-, di-, tri-, poly-, and oligosaccharides; sugars such assucrose, glucose (corn syrup), dextrose, invert sugar, fructose,maltodextrin and polydextrose; saccharin and salts thereof such assodium and calcium salts; cyclamic acid and salts thereof; dipeptidesweeteners; chlorinated sugar derivatives such as sucralose anddihydrochalcone; sugar alcohols such as sorbitol, sorbitol syrup,mannitol, xylitol, hexa-resorcinol, and the like, and combinationsthereof. Hydrogenated starch hydrolysate, and the potassium, calcium,and sodium salts of3,6-dihydro-6-methyl-1-1,2,3-oxathiazin-4-one-2,2-dioxide many also beused.

Flavorants

In some embodiments, it may be beneficial to include a flavorant in thecompositions of the invention. Flavorants help improve the palatabilityof the composition by conferring a more desirable taste to thecomposition. Flavorants are well known in the art. Accordingly, theflavorants described herein are not intended to constitute an exhaustivelist, but are provided merely as exemplary flavorants that may be usedin the compositions and methods of the invention. Exemplary flavorantsinclude, without limitation, natural and/or synthetic (i.e., artificial)compounds such as mint, peppermint, spearmint, wintergreen, menthol,anise, cherry, strawberry, watermelon, grape, banana, peach, pineapple,apricot, pear, raspberry, lemon, grapefruit, orange, plum, apple, lime,fruit punch, passion fruit, pomegranate, chocolate (e.g., white, milk,dark), vanilla, caramel, coffee, hazelnut, cinnamon, combinationsthereof, and the like.

Coloring Agents

Coloring agents can be used to color code the composition, for example,to indicate the type and dosage of the therapeutic agent therein.Coloring Agents are well known in the art. Accordingly, the coloringagents described herein are not intended to constitute an exhaustivelist, but are provided merely as exemplary coloring agents that may beused in the compositions and methods of the invention. Exemplarycoloring agents include, without limitation, natural and/or artificialcompounds such as FD & C coloring agents, natural juice concentrates,pigments such as titanium oxide, silicon dioxide, and zinc oxide,combinations thereof, and the like.

Combination Therapy

As described above, the compositions and methods of the invention may beused to treat PTSD, depression, fibromyalgia, traumatic brain injury,sleep disorder, non-restorative sleep, chronic pain, and anxietydisorder. Any of the methods of treatment described also may be combinedwith a psychotherapeutic intervention to improve the outcome of thetreatment. Exemplary psychotherapeutic interventions directed at eithermodifying traumatic memories or reducing emotional responses totraumatic memories, including psychological debriefing, cognitivebehavior therapy and eye movement desensitization and reprocessing,systematic desensitization, relaxation training, biofeedback, cognitiveprocessing therapy, stress inoculation training, assertiveness training,exposure therapy, combined stress inoculation training and exposuretherapy, combined exposure therapy, and relaxation training andcognitive therapy. In each case, the goal of the intervention involveseither modifying traumatic memories or reducing emotional responses totraumatic memories. The intended result is generally a improvement inthe symptoms of PTSD or the reduction of occurrences of symptoms, asevidenced in terms of physiological responding, anxiety, depression, andfeelings of alienation.

In some embodiments of the invention, a composition is combined with adrug which may further alleviate the symptoms of PTSD, depression,fibromyalgia, traumatic brain injury, sleep disorder, non-restorativesleep, chronic pain, or anxiety disorder. The drugs include analpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, ananticonvulsant, a selective serotonin reuptake inhibitor, aserotonin-norepinephrine reuptake inhibitor, and an analgesic. Exemplaryanticonvulsants include carbamazepine, gabapentin, lamotrigine,oxcarbazepine, pregabalin, tiagabine, topiramate, and valproate. Anexemplary alpha-1-adrenergic receptor antagonist is prazosin. Exemplaryselective serotonin reuptake inhibitors or serotonin-norepinephrinereuptake inhibitors include, bupropion, citalopram, desvenlafaxine,duloxetine, escitalopram, fluoxetine, escitalopram, fluvoxamine,milnacipran, paroxetine, sertraline, trazodone, and venlafaxine.Exemplary analgesics include pregabalin, gabapentin, acetaminophen,tramadol, and non-steroidal anti-inflammatory drugs (e.g., ibuprofen andnaproxen sodium). Additional drugs that can be used in combination withthe compositions of the invention include sodium oxybate, zolpidem,pramipexole, modafinil, temazepam, zaleplon, and armodafinil.

It is to be understood that the embodiments of the present inventionwhich have been described are merely illustrative of some of theapplications of the principles of the present invention. Numerousmodifications may be made by those skilled in the art based upon theteachings presented herein without departing from the true spirit andscope of the invention.

The following examples are set forth as being representative of thepresent invention. These examples are not to be construed as limitingthe scope of the invention as these and other equivalent embodimentswill be apparent in view of the present disclosure, figures, andaccompanying claims.

EXAMPLES Example 1

Thermal analytical techniques were used to assess the compatibility of adrug product (tablet) containing Cyclobenzaprine HCl (API). Thecompatibility assessment was carried out between the API and a number ofpossible excipients in a 1:1 ratio. Based on the thermal events recordedfor each component and for the mixtures, the analyses were carried outby investigating the peaks recorded by differential scanning calorimetry(DSC) in mixture between API and the excipients. Differences in thermalprofiles between the single compound and the related mixture obtainedafter milling the products in an agate mortar were evaluated. Stabilityand compatibility also were also assessed on the final drug productafter stress conditions at 40° C. and 50° C. for one month.

The following raw materials were used:

Cyclobenzaprine HCl

Sodium stearyl fumarate

Potassium Phosphate Bibasic Crospovidone (Kollidon CL) Silicon Colloidal

Pearlitol flash

Opadry 03F190003 Clear Opadryll 85F19000 Clear

A “formulation ratio” mixture was made with the following composition:2.40 mg Cyclobenzaprine HCl, 31.55 mg Mannitol and Maize starch, 2.00Crospovidone, 0.50 mg colloidal silica, 0.050 mg Sodium StearylFumarate, and 1.05 Potassium hydrogen phosphate.

Aliquots of API and each excipient were weighed in a ratio of 1:1(unless specified otherwise) and ground in an agate mortar. Thehomogeneous mixtures then were analyzed.

Differential Scanning Calorimetry (DSC)

The DSC heating curves were obtained with a TA 821 DSC Mettlerinstrument under the following conditions:

Heating rate: 10° C./minAmbient: Nitrogen 30 mL/minSample holder: normal open aluminum panTemperature range: from 25° C. to 250° C.Instrument calibration: Indium sample purity 99.999%

With Cyclobenzaprine HCl alone, melting with decomposition was detectedbetween 210° C. and 223° C. (onset at 215.2° C., ΔH=−96.5 J/g) (FIG. 1).

In a 1:1 mixture of Cyclobenzaprine HCl and Sodium Stearyl fumarate, theendothermic transitions of sodium stearyl fumarate were recorded in therange of 100° C. to 120° C. (FIG. 2). No API transition peak wasdetected, but a physical interaction was observed.

In a 1:1 mixture of Cyclobenzaprine HCl and Sodium Stearyl fumarate, theendothermic transitions of sodium stearyl fumarate were recorded in therange of 90° C. to 120° C. (FIG. 3). The API transition peak wasdetected between 192° C. and 216° C. (onset at 202.31° C., ΔH=−50.5J/g). A small physical interaction was observed. This interaction likelyoccurred during tablet compression when a possible rise in temperaturecan induce changes in the API.

In a 1:1 mixture of Cyclobenzaprine HCl and Potassium phosphate bibasic,a chemical interaction (acid-base) was observed between API andexcipient. A transition between 40° C. and 60° C. was observed (FIG. 4),while, at high temperatures, the API melting peak was slightly visible.

In the formulation ratio, a peak was observed at 47° C., likely due towater absorption by K₂HPO₄ while the API melting peak was detectedbetween 182° C. and 210° C. (onset at 195.6° C., ΔH=−31.4/g) (FIG. 5). Asmall interaction was observed at higher temperatures.

In a 1:1 mixture of Cyclobenzaprine HCl and Crospovidone (Kollidon CL),the release of imbibition water was recorded between 30° C. and 110° C.,followed by the melting/decomposition of API between 210° C. and 223° C.(onset at 214.4° C., ΔH=−37.4 J/g) (FIG. 6). No interaction wasdetected.

In a 1:1 mixture of Cyclobenzaprine HCl and Silicon (colloidal), the APImelting/decomposition peak was recorded between 186° C. and 221° C.(onset at 207.2° C., ΔH=−41.4 J/g) (FIG. 7). No interaction wasdetected, only a lowering of the degree of crystallinity.

In a 1:1 mixture of Cyclobenzaprine HCl and Pearlitol Flash®, a physicalcomplex interaction peak (eutectic) was surprisingly observed in therange of 130° C. to 168° C. (onset at 143.2° C., ΔH=−151.8 J/g) (FIG.8). No API transition melting was detected, only a physical complexfusion at lower temperatures.

In the formulation mixture, because the ratio is about 13:1Pearlitol®:API, the melting peak of Pearlitol® was detected between 150°C. and 173° C. (onset at 162.0° C., ΔH=−172.2 J/g) (FIG. 9), preceded bya small peak at 137° C. to 151° C. (onset at 142.2° C., ΔH=−12.2 J/g)due to the eutectic between the two components. The same behavior wasobserved in the 1:1 mixture.

In a 1:1 mixture of Cyclobenzaprine HCl and Opadry Clear, the PEGtransitions were easily visible between 46° C. and 64° C., followed byan API melting/decomposition peak between 180° C. and 218° C. (onset at199.0° C., ΔH=−45.5 J/g) (FIG. 10). The interaction is due to the meltedOpadry.

In a 1:1 mixture of Cyclobenzaprine HCl and Opadry II Clear, the PEGtransitions were easily visible between 44° C. and 65° C., followed bythe interaction peak between PVA (Polyvinyl Alcohol) and API, in therange of 44° C. to 213° C. (onset at 154.9° C., ΔH=−32.5 Jig) (FIG. 11)that could be due to the partial solubilization of the API by theexcipients.

In the formulation mixture, only one thermal event was recorded between124° C. and 170° C. (onset at 157.0° C., ΔH=−164.1 Jig) (FIG. 12). Theevent was cause by Pearlitol Flash® which, due to its amount, coveredall the other transitions. Moreover, the API with Pearlitol gave aeutectic (physical interaction at the solid state) that was detected at142° C. This physical interaction can stabilize the formula and preventother interactions with excipients (e.g., Opadry I, Opadray II, andK₂HPO₄).

To evaluate the interaction between the API and the excipient, thermalinvestigations were conducted on a tablet stored for 1 month at 40° and50° C. The data recorded were compared with the thermal profile of thesame batch analyzed at time zero. Two thermal events for CyclobenzaprineHCl were recorded: a first of a small entity at 146.0° C., and a secondbetween 136° C. and 170° C. (onset at 158.3° C., ΔH=−143.2 J/g) (FIG.13), mainly due to melting of Pearlitol flash.

Two thermal events were recorded for Cyclobenzaprine HCl at 40° C.: thefirst one of small entity at 145.8° C., and the second between 134° C.and 171° C. (onset at 156.7° C., ΔH=−169.7 J/g) (FIG. 14), mainly due tomelting of Pearlitol Flash®. Two thermal events also were recorded forCyclobenzaprine HCl at 50° C.: the first one of small entity at 146.5°C., and the second between 137° C. and 179° C. (onset at 158.4° C.,ΔH=−163.3 J/g) (FIG. 15), mainly due to melting of Pearlitol Flash®. Thethermal behaviors recorded were similar, and no interactions wereobserved in the tablet after storage at 40° C. and 50° C. Theinteraction recorded for the binary mixtures was no longer observed,likely due to the dilution of the API by the Pearlitol Flash® excipientand reduced contact between API and the lubricant sodium stearylfumarate.

In summary, different types of interaction were observed among theexcipients and the API. A physical interaction was observed with SodiumStearyl fumarate, especially in the 1:1 ratio, likely due to partial APIsolubilization or reactions at the particles' surfaces between the Cl⁻and Na⁺ counter ions. In the formulation ratio, this incompatibilitydisappears. Even in a formulation tested for stability at 40° C. and 50°C. for one month, this interaction was not seen. A chemical (acid-base)interaction was observed with Potassium phosphate bibasic, both in 1:1and in formulation ratios. No interaction was observed with Silicon(colloidal) and Kollidon. A eutectic interaction was observed withPearlitol Flash®, due to the presence of mannitol. In the formulationratio (about 13:1 excipient:API), the thermal transition of the API wascompletely shifted by excipient complex formation (eutectic). Theinteraction with Opadry Clear is small and is due to PEG contributionsthat preceded the API Transition. The interaction with Opadry II Clearis evident and could be due to the presence of PVA (Polyvinyl Alcohol)that partially solubilizes the API. Table D summarizes the observationsof the various excipients with Cyclobenzaprine HCl API.

TABLE D Excipient reactions with API Mixture in Excipient Mixture 1:1formulation ratio Sodium stearyl fumarate Physical interaction Nointeraction Potassium phosphate Acid - base interaction Low chemicaldibasic interaction Crospovidone (Kollidon No ND CL) Silicon (colloidal)No ND Pearlitol Flash ® Eutectic Eutectic Opadry Clear Chemical (small)ND Opadry II Clear Chemical ND ND: Not determined

Example 2

As described above, thermal analytical techniques were further used toassess the compatibility of a drug product (tablet) containingCyclobenzaprine HCl (API). The compatibility assessment was carried outbetween the API and additional excipients in a 1:1 ratio. The 1:1API-excipient mixtures were formed in two different ways: first, bymixing only, and second, by strong milling in an agate mortar. Thethermal behavior recorded in the two different mixtures were comparedwith those of the single components. On the basis of thermal eventsrecorded for each component and for the mixtures, the analyses werecarried out by investigating the meanings of the peaks recorded bydifferential scanning calorimetry (DSC) in mixtures between the API andthe excipients. Furthermore, in order to define the nature of theinteraction, the Fourier Transformate Infra Red Spectroscopy with TotalAttenuated Reflectance (FT-IR/ATR) and X-ray powder diffraction (XRPD)of some samples (API, excipient, and mixed and milled mixtures) wascarried out and compared.

The following raw materials were used:

Cyclobenzaprine HCl

Di Sodium phosphate anhydrousDi Sodium phosphate dihydrateDi Sodium phosphate heptahydrateTrisodium citrate dihydrate

Effersoda® Sorbitol Mannitol

Mix API+Di Sodium phosphate anhydrousMix API+Di Sodium phosphate dihydrateMix API+Di Sodium phosphate heptahydrateMix API+Trisodium citrate dihydrate

Mix API+Effersoda® Mix API+Sorbitol Mix API+Mannitol

Trisodium citrate anhydrous

Disodium Glycine Carbonate

Mix API+Trisodium citrate anhydrous

Mix API+Disodium Glycine Carbonate

Aliquots of API and each excipient were weighed in a ratio of 1:1 andground in an agate mortar. Then, the homogeneous mixtures were analyzed.These sample mixtures were labeled “B”, while the mechanical-onlymixtures were labeled “A.”

Differential Scanning Calorimetry (DSC)

The DSC heating curves were obtained by TA 821 DSC Mettler instrumentunder the following conditions:

Heating rate: 10° C./minAmbient: Nitrogen 30 mL/minSample holder: normal open aluminum panTemperature range: from 25° C. to 250° C.Instrument calibration: Indium sample purity 99.999%Fourier Transformate Infra Red Spectroscopy with Total AttenuatedReflectance (FT-IR/ATR)

The FT-IR spectra were collected with a Perkin Elmer spectrum Twoinstrument with air as background and 4 cm⁻¹ resolution.

X-Ray Powder Diffraction (XRPD)

X-ray powder diffraction (XRPD) tests were performed with the ULTIMA IVinstrument (Rigaku), laying the sample on a static sample holder. TheX-ray focusing slit has a variable width, interlocked with the q value.The X-ray tube has a Copper target, with a current intensity of 40 mAand a voltage of 40 kV. Radiation was generated by the Cockcroft-Waltonmethod, and was constituted by K_(α1) (1.540562 Å) and K_(α2) (1.544398Å). The analytical conditions were:

Fixed Time; sampling width 0.02 deg, scanning rate 1.3 s/step, 2 q range3.35 deg and sample holder; amorphous glass equiangular 9200/2G, 0.2 mmdeep. The sample was pressed with a glass plate.

Decomposition of Cyclobenzaprine HCl with melting was detected between210° C. and 225° C. (onset at 215.6° C., ΔH=−105.0 J/g) (FIG. 16). TheDSC heating curves of the mixtures in comparison with the API

and excipients (mixtures A and B) were then analyzed. The interactionpeak for a 1:1 Cyclobenzaprine HCl−sodium phosphate anhydrous mixture(mixture A) was recorded in the range of 167° C. to 220° C. (onset at197.0° C., ΔH=−109.6 J/g). A physical interaction was observed andcharacterized by the lowering of API melting (FIG. 17). The interactionpeak for a 1:1 Cyclobenzaprine HCl−sodium phosphate anhydrous mixture(mixture B) was recorded in the range of 172° C. to 201° C. (onset at180.9° C., ΔH=−31.1 J/g). A physical interaction was observed (FIG. 18).By comparing the mixtures A and B, it is evident that the interaction ispresented more in the milled mixture (FIG. 19).

The release of crystallization water from sodium phosphate in a 1:1mixture of Cyclobenzaprine HCl and sodium phosphate dihydrate (mixtureA) was observed between 57° C. and 108° C. (onset at 73.4° C., ΔH=−227.8J/g), followed by the interaction peak in the range of 174° C. to 220°C. (FIG. 20). This effect was composed by two small effects: a physicalinteraction and partial solubilization. Few peaks on the plot wereobserved, likely due to release of small amount of water in a meltedmatrix. The release of crystallization water in a 1:1 mixture ofCyclobenzaprine HCl and sodium phosphate dihydrate (mixture B) wasrecorded between 61° C. and 100° C. (onset at 71.8° C., ΔH=−239.8 J/g),followed by the interaction peak in the range of 160° C. to 221° C.(onset at 178.7° C., ΔH=−116.5 J/g) (FIG. 21). A physical interactionwas observed. FIG. 22 shows a comparison between mixtures A and B. Theinteraction is more evident in the milled

mixture. The water present in the excipient can modify the mixture andreduce the API stability.

The release of crystallization water in a 1:1 mixture of CyclobenzaprineHCl and sodium phosphate heptahydrate (mixture A) (in two differentsteps) was recorded between 39° C. and 68° C. (onset at 47.2° C.,ΔH=−77.6 J/g) and between 67° C. and 96° C. (onset at 73.8° C., H=−68.9J/g), followed by the interaction peak in the range of 176° C. to 220°C. (onset at 199.5° C., ΔH=−83.4 J/g) (FIG. 23). With mixture B,crystallization water was released (in two different steps) between 43°C. to 54° C. (onset at 45.9° C., ΔH=−49.6 J/g) and between 73° C. and98° C. (onset at 77.8° C., ΔH=−151.7 J/g), followed by the interactionpeak in the range of 174° C. to 215° C. (onset at 174.5° C., ΔH=−55.4J/g) (FIG. 24). FIG. 25 shows a comparison between mixtures A and B. Theinteraction was anticipated in the milled mixture and showed two events,relating to the interaction peak and to a residual of API. The waterpresent in the excipient induced physical changes of the API, even atlow temperatures.

Crystallization water was released and decomposition (complex peak) of a1:1 mixture of Cyclobenzaprine HCl and trisodium citrate dihydrate(mixture A). was recorded between 154° C. and 183° C. (onset at 167.1°C., ΔH=−127.6 J/g), followed by the interaction peak in the range of186° C. to 227° C. (onset at 197.2° C., ΔH=−102.6 J/g) (FIG. 26). Aphysico-chemical interaction was observed. The release ofcrystallization water and excipient decomposition (complex peak) inmixture B were recorded between 146° C. and 181° C. (onset at 157.9° C.,ΔH=−179.4 J/g), followed by the interaction peak in the range of 180° C.to 216° C. (onset at 190.5° C., ΔH=−88.7 J/g). A physico-chemicalinteraction was observed (FIG. 27). The decomposition of trisodiumcitrate was similar in mixtures A and B (FIG. 28).

A release of CO₂ was recorded in a 1:1 Cyclobenzaprine HCl-Effersoda®mixture (mixture A) between 99° C. and 187° C. (onset at 109.5° C.,ΔH=−308.0 J/g), followed by the melting of API in the range of 193° C.to 218° C. (onset at 203.2° C., ΔH=−46.8 J/g) (FIG. 29). The physicalinteraction observed was small, but due to excipient instability; theAPI melting peak was anticipated and interaction occurred. Mixture Bresulted in a release of CO₂ between 104° C. and 210° C. (onset at132.9° C., ΔH=−399.6 J/g) and disappearance of the API peak (FIG. 30). Aphysico-chemical interaction was observed. In comparing mixtures A andB, the interaction of mechanical mixture was lower, while the milledmixture was higher. Also, the release of CO₂ by Effersoda® covered theAPI behavior, due to possible interactions (FIG. 31).

In a 1:1 mixture of Cyclobenzaprine HCl and sorbitol (mixture A), themelting of sorbitol covered the API melting peak. The event was recordedbetween 81° C. and 108° C. (onset at 96.7° C., ΔH=−88.2 J/g) (FIG. 32).An interaction was observed, due to the solubilization of API bysorbitol. With mixture B, the melting of sorbitol also covered the APImelting peak. The event was recorded between 82° C. and 107° C. (onsetat 95.3° C., ΔH=−87.3 J/g) (FIG. 33). An interaction was observed, dueto the solubilization of API by sorbitol. The interaction was comparablein both mixtures A and B (FIG. 34). To confirm that sorbitol, during themixture, solubilized the API, an XRPD investigation was carried out(FIG. 35). The mixture presented several peaks of sorbitol and very fewof Cyclobenzaprine HCl. The broadening of the baseline was indicative ofamorphous phases, due to the matrix melting.

Surprisingly, a physical complex interaction peak (eutectic) wasobserved in the range of 137° C. to 170° C. (onset at 147.3° C.,ΔH=−164.6 J/g) in a 1:1 Cyclobenzaprine HCl-mannitol mixture (mixture A)(FIG. 36). No API transition melting was detected, only the melting of aeutectic at a lower temperature. With mixture B, a physical complexinteraction peak (eutectic) also was observed in the range of 132° C. to167° C. (onset at 141.5° C., H=−153.4 J/g) (FIG. 37). No API transitionmelting was detected, only the melting of eutectic at a lowertemperature. The interaction was comparable in both the mixtures (FIG.38).

In a 1:1 mixture of Cyclobenzaprine HCl and Trisodium Citrate anhydrous(mixture A), the interaction peak was observed in the range of 168° C.to 215° C. (onset at 188.8° C., ΔH=−102.4 J/g) (FIG. 39). No APItransition melting was detected, only a physical complex melting at alower temperature. The interaction peak was observed in the range of158° C. to 211° C. (onset at 167.7° C., H=−110.1 J/g) in mixture B (FIG.40). No API transition melting was detected, only a physical complexmelting at lower temperature. In comparing the milled and mixedmixtures, the interaction was more evident in the milled mixture (FIG.41).

In a 1:1 mixture of Cyclobenzaprine HCl and Disodium Glycine carbonate(Mixture A), a broad interaction peak was observed in the range of 155°C. to 231° C. (onset at 180.7° C., H=−79.3 J/g) (FIG. 42). No APItransition melting was detected, only a physical complex melting at alower temperature. Mixture B produced an interaction peak in the rangeof 155° C. to 231° C. (onset at 184.0° C., H=−77.0 J/g) (FIG. 43). NoAPI transition melting was detected, only a physical complex melting ata lower temperature. The interaction was comparable in both the mixtures(FIG. 44)

FT-IR/ATR

To define the nature of the interactions observed by DSC and understandif the thermal treatment, during the temperature rise, was the rootcause of the different DSC profiles, FT-IR/ATR spectroscopyinvestigation was carried out. In FIGS. 45-47, the FT-IR/ATR spectra ofCyclobenzaprine HCl and Trisodium Citrate anhydrous (mixture A) areshown in superimposition, in different regions. In the mixture, thepresence of all the bands of both API and excipient were observed. Inparticular, in the 3000-2000 cm⁻¹ region (FIG. 45), the band ofchlorohydrate was still well visible, as a sign that no chemicalacid-base reaction had occurred. In FIG. 48, the superimposition ofmixtures A and B shows that no substantial modifications were observed.

FIGS. 49-51 show the FT-IR/ATR spectra of Cyclobenzaprine HCl andDisodium Glycine Carbonate (mixture A) in superimposition, in differentregions. In the mixture, all bands of both API and excipient wereobserved. In particular, in the 3000-2000 cm⁻¹ region (FIG. 49), theband of chlorohydrate was still visible, as a sign that no chemicalacid-basis reaction occurred. FIG. 52 depicts the superimposition ofmixtures A and B. No substantial modifications were observed. From theFT-IR/ATR spectra, the thermal transitions recorded originated from theheating of the mixtures, but, at room temperature, the two componentswere stable and did not interact.

In summary, different types of interaction were observed among theexcipients and the API. With all the basic excipients investigated(especially the hydrates), interactions were observed. The interactionsseemed to be acid/base type reactions, possibly between the cation Naand the HCl of the drug substance. The interaction was more evident inmilled mixtures, because the contact between API and excipient particleswas deeper and closer. With sorbitol, a physical interaction wasobserved, due to the solubilization of the API in the melted excipient,while with mannitol, the formation of a eutectic was surprisinglyobserved. The interaction with trisodium citrate anhydrous and disodiumglycine carbonate was only physical and occurred at high temperatures asshown by FT-IR/ATR spectroscopy. Table B shows a summary of theinteractions between the API and excipients for the mixed and milledmixtures.

TABLE B Interactions between Cyclobenzaprine HCl and excipientsExcipient Mixture 1:1 (mixed) Mixture 1:1 (milled) Di Sodium phosphateLow chemical Low chemical anhydrous Di Sodium phosphate ChemicalChemical dihydrate Di Sodium phosphate Chemical Chemical heptahydrateTrisodium citrate Chemical Chemical dihydrate Effersoda ® Low chemicalChemical Sorbitol Chemical Chemical Mannitol Eutectic Eutectic TriSodium Citrate Physical Physical anhydrous Di Sodium Glycine PhysicalPhysical carbonate

Example 3

The compatibility of mannitol with Cyclobenzaprine HCl was investigatedby differential scanning calorimetry (DSC), and the resultinginteractions were assessed. In particular, the formation of a eutecticbetween the mannitol and the Cyclobenzaprine HCl during mixing improvedthe cohesion between the particles and provided better physical bondingbetween the Cyclobenzaprine HCl active pharmaceutical ingredient (API)and the mannitol excipient. Additionally, the physical state preventsthe erosion of a dosage form for cyclobenzaprine administration.

The interaction between Cyclobenzaprine HCl and Pearlitol Flash® (anexcipient containing mannitol) is an invariant physical interactionbecause it is in thermal equilibrium in which the two components arewell mixed and stabilized. Physically, this means that the meltedeutectic, solid eutectic, and solid mannitol all coexist at the sametime and are in chemical equilibrium. The resulting solid macrostructurefrom the eutectic reaction depends on a few factors, including that thetwo solid solutions nucleate and grow together during a mechanicalmixture.

Because mannitol is a common excipient in solid drug formulations, itwas examined for compatibility with Cyclobenzaprine HCl was investigatedusing DSC and interactions occurring were assessed. Surprisingly, theformation of a eutectic during mechanical mixing was discovered. Toconfirm the formation of a eutectic and to characterize its physicalproperties, several binary mixtures at different ratios of API andexcipient were prepared and analyzed by DSC and by XRPD. The eutecticformation improved the cohesion between the API and excipient particlesand assured better physical linking between the two.

In order to confirm the eutectic formation and to characterize itsphysical properties, several binary mixtures at different ratios ofAPI-excipient were prepared and analyzed by DSC and by X-ray powderdiffraction (XRPD). The mixtures were obtained by gently milling inagate mortar of micronized Cyclobenzaprine HCl and mannitol, in order toobtain homogeneous distribution of the particles. For each DSC heatingcurve, the onset temperature and the enthalpy were evaluated both forthe eutectic contribute and for the excess of component. The recordedvalues were plotted and a phase diagram between the two components wasobtained with a characteristic profile of phase diagrams of eutecticmixtures.

Mixtures also were investigated by XRPD and compared with the patternsof pure components. These analyses were carried out to confirm that theeutectic compound is only a physical interaction between the twoproducts and not a formation of a new entity with different chemicalproperties. The XRPD patterns obtained in the mixtures, compared withpure components, were plotted in order to confirm the linearity of thepeak intensities (cpf) of mannitol and Cyclobenzaprine HCl, and aproportional peak height at characteristic 2 theta angles.

Aliquots of Cyclobenzaprine HCl API and Mannitol were weighed in theratios described below and ground in an agate mortar, and thehomogeneous mixtures subsequently analyzed.

Mixture API amount (%) 1 15 2 30 3 40 4 45 5 50 6 65 7 75 8 80 9 90 1095

Differential Scanning Calorimetry (DSC)

DSC heating curves were obtained using a TA 821 DSC Mettler instrumentunder the following conditions:

Heating rate 10° C./min Ambient Nitrogen 30 mL/min Sample order Normalopen aluminum pan Temperature range From 25° C. to 250° C. Instrumentcalibration Indium sample purity 99.999%

X-Ray Powder Diffraction (XRPD)

X-ray powder diffraction (XRPD) tests were performed with a ULTIMA IV(Rigaku) instrument, laying the sample on a static sample holder. TheX-ray focusing slit had a variable width, interlocked with the 0 value.The X-ray tube had a Copper target, with a current intensity of 40 mAand a voltage of 50 kV. The radiation generated by the Cockcroft-Waltonmethod is constituted by K_(α1) (1.540562 Å) and K_(α2) (1.544398 Å).The analytical conditions were as follows:

Fixed Time: Sampling width, 0.02 deg; Scanning rate, 1.0 s/step2 θ range: 3/50 deg.Sample holder: amorphous glass—equiangular 9200/2G, 0.2 mm deep. Thesample was pressed with a glass plate.

Pure components of Cyclobenzaprine HCl and mannitol, as well as mixturesof the two, were analyzed with DSC (Table A). FIG. 53 depicts themelting curve with 100% Cyclobenzaprine HCl. Melting with decompositionwas detected between 210° C. and 221° C. (onset at 215.5° C., ΔH=−100.6J/g). FIG. 54 depicts the melting curve with 100% mannitol. Melting wasdetected between 151° C. and 173° C. (onset at 164.4° C., ΔH=−256.8J/g). Figs. C-L depict the various mixtures. Table A summarizes thedata.

TABLE A Summary of DSC data T onset T onset 2nd ΔH ΔH 2nd ΔH % eutecticeffect eutectic effect global % API Mannitol (° C.) (° C.) (J/g) (J/g)(J/g) Plot 100 0 — 215.5 — 100.57 — FIG. 53 0 100 — 164.37 — — 256.81FIG. 54 15 85 141.38 161.21 28.78 190.27 219.77 FIG. 55 30 70 142.63157.57 68.4 134.01 202.88 FIG. 56 40 60 142.69 154.86 88.09 102.08190.55 FIG. 57 45 55 143.43 156.47 99.55 56.41 157.25 FIG. 58 50 50142.94 155.41 109.8 44.06 174.12 FIG. 59 65 35 143.61 151.21 130.53 4.6134.58 FIG. 60 75 25 143.64 143.64 92.7 — — FIG. 61 80 20 143.36 177.6987.8 0.73 — FIG. 62 90 10 143.57 197.69 46.05 3.14 — FIG. 63 95 5 142.1204.9 15.23 45.14 — FIG. 64

The above results demonstrated that the eutectic composition formed atapproximately 75% Cyclobenzaprine HCl (API) and 25% mannitol. Under 75%,two distinct melting peaks were observed from the melting of theeutectic fraction and the excess of the individual components. FIG. 65shows a phase diagram depicting the onset melting temperatures of theeutectic fraction and the excess components, plotted as function of APIpercentage. Five distinct zones are present in the diagram:

Zone A: Excess of Mannitol (liquid eutectic+solid mannitol)Zone B: Excess of Cyclobenzaprine HCl (liquid eutectic+solidCyclobenzaprine HCl)Zone C: Solid eutectic with mannitolZone D: Solid eutectic with Cyclobenzaprine HClZone E: Liquid phase with mannitol and Cyclobenzaprine HCl

In Zone A, when the percentage of API increased, the onset temperatureof the excess of mannitol decreased while the temperature of eutecticfraction remained constant around 143° C. Above the eutecticcomposition, the excess of API led to an increase in the temperature(Zone B). In addition, there was a good correlation between mixtures andtemperature. A few small deviations from the trend curve were due to aincompletely homogeneous powder mixture.

FIG. 66 shows eutectic melting enthalpy as function of the APIpercentage. The eutectic melting enthalpy increases until the eutecticcomposition is attained. At the eutectic composition, the maximum valueshould be reached, but, due to partial decomposition of the product, itwas not possible to correctly evaluate the melting heat. Instead, theplot shows the theoretical value, obtained on the basis of the meltingenthalpy of the pure compounds. The eutectic composition corresponds to75% API, 25 Mannitol, by weight. The theoretical ratio between themolecular weights (311.38 mw/182.17 mw) was 1.71, while the ratio fromthe weight percentage [(0.75/311.38 mw)/(0.25/182.17 mw)] gives a molarratio for the eutectic of 1.76 (i.e., 1.76 moles of Cyclobenzaprine HClto 1 mole of Mannitol in the eutectic).

XRPD

To confirm that the eutectic composition was only a physical mixture andthat a new entity or adduct was not formed, the mixtures were analyzedby X-ray Powder Diffraction, where no thermal treatments were applied(pure Cyclobenzaprine HCl, Figs. O-P; pure mannitol, Figs. Q-R). Fig Sdepicts the stacking of pure mannitol, API, and the eutectic mixture at75%, showing different diffraction zones where no peaks of the purecomponents were distinguishable and no interferences were detected. FIG.72 shows the stacking of pure mannitol and API and mixtures thereof,where it was possible to point out three distinct diffraction ranges:Mannitol 14.1-15.0° 2θ, API 12.5-13.3° 2θ and 17.5-18.2° 2θ.

Within these ranges, an evaluation was carried out for each mixtureanalyzed (30, 50, 65, 75 and 90%). Each peak height was plotted asfunction of API % and linearity coefficient was obtained (Figs. U-V).Good correlations between concentration and peak heights were obtained.API and mannitol, when mixed, resulted in no adduct formation, only aphysical eutectic formation.

In summary, the data show that thermal behavior of the mixtures presentstwo endotherms, relating to the eutectic and to the melting of theexcess of the main component. Thermal entities recorded for the mixturesagreed with the percentage of API/Mannitol ratio present in the eutecticmixture. At the eutectic composition, only one melting peak was visible.The eutectic composition was reached at about 75% API and 25% Mannitol.The eutectic composition confirmed the molar stoichiometry (ratiobetween the two components: 1.76). The melting temperature of theeutectic was about 143.6° C. and was recorded for all the investigatedmixtures. By XRPD, no adduct interaction occurred between API andmannitol, only a physical eutectic formation.

Example 4

Thermal analytical techniques were used to assess the compatibility ofthe drug product amitriptyline HCl. The compatibility assessment wascarried out between the API and the excipients in a 1:1 ratio. On thebasis of thermal events recorded for each component and for themixtures, the analyses were carried out by investigating the peaksrecorded by DSC in mixtures between API and the excipients. Differencesin thermal profiles between the single compound and the related mixtureswere obtained after milling the products in an agate mortar.

DSC was performed substantially as described in Examples 1 and 2. Thefollowing raw materials were used:

Amitriptyline HCl

Sodium stearyl fumarateStearic acidGlycerol dibehenateMagnesium stearatePearlitol flash

Pearlitol 200 SO/Mannitol

Unipure DW/Corn starch pregelatinized

Crospovidone—Kollidon CL Silicon Colloidal/Aerosil 200

Sodium phosphate dibasicSodium bicarbonateSodium carbonateSodium Phosphate dodecahydrateSodium Phosphate anhydrous.

The melting and decomposition of 100% Amitriptyline HCl was detectedbetween 192° C. and 202° C. (onset at 195.1° C., ΔH=−93.9 J/g) (FIG.75).

In a 1:1 mixture of a amitriptyline HCl and Sodium Stearyl fumarate, theendothermic transitions of sodium stearyl fumarate were recorded in therange of 90° C. to 120° C. (FIG. 76). No API transition peak wasdetected, and a physical interaction was observed.

The endothermic transitions of stearic acid in a 1:1 mixture ofAmitriptyline HCl and Stearic acid were recorded in the range of 47° C.to 64° C. The API transition peak was detected between 179° C. and 195°C. (onset at 181.1° C., ΔH=−5.15 J/g) (FIG. 77). A small physicalinteraction was observed.

In a 1:1 mixture of Amitriptyline HCl and glycerol dibehenate (orglycerol behenate), the endothermic transitions of glycerol dibehenatewere recorded in the range of 63° C. to 74° C. The API transition peakwas detected between 186° C. and 199° C. (onset at 189.0° C., ΔH=−31.0J/g) (FIG. 78). A small physical interaction was observed.

In a 1:1 mixture of Amitriptyline HCl and Magnesium stearate, theendothermic transitions of magnesium stearate were recorded in the rangeof 100° C. to 120° C. The API transition peak was detected between 169°C. and 187° C. (onset at 174.0° C., ΔH=−10.6 J/g) (FIG. 79). A smallphysical interaction was observed.

In a 1:1 mixture of Amitriptyline HCl and Pearlitol Flash®, amannitol-containing excipient, a physical complex interaction peak(eutectic) was observed in the range of 130° C. to 170° C. (FIG. 80). NoAPI transition melting was detected, only a physical complex fusion atlower temperature. The eutectic melting point corresponds to 135.1° C.(the onset value) (FIG. 81).

In a 1:1 mixture of Amitriptyline HCl and Pearlitol 200 SD/Mannitol, aphysical complex interaction peak (eutectic) was observed in the rangeof 130° C. to 170° C. (FIG. 82). No API transition melting was detected,only a physical complex fusion at lower temperature. The eutecticmelting point corresponds to 132.8° C. (the onset value) (FIG. 83). Thedifference in melting temperatures of about 2° C., as compared to themixture with only Pearlitol flash, is due to the presence of additionalmannitol in this mixture.

The release of imbibition water in a 1:1 mixture of Amitriptyline HCland Unipure DW/Corn starch (partially pregelatinized) was recordedbetween 30° C. and 110° C., followed by the melting of API between 178°C. and 199° C. (onset at 181.9° C., ΔH=−28.2 J/g) (FIG. 84). Nointeraction was detected

In a 1:1 mixture of amitriptyline HCl and Crospovidone (Kollidon CL),the release of imbibition water was recorded between 30° C. and 100° C.,followed by the melting/decomposition of API between 192° C. and 200° C.(onset at 194.4° C., ΔH=−41.3 J/g) (FIG. 85). No interaction wasdetected.

In a 1:1 mixture of Amitriptyline HCl and Silicon (colloidal), the APImelting peak was recorded between 188° C. and 200c° C. (onset at 193.7c°C., ΔH=−17.2 J/g) (FIG. 86). No interaction was detected, only alowering of the degree of crystalline Amitriptyline HCl.

The endothermic transitions of sodium phosphate dibasic in a 1:1 mixtureof Amitriptyline HCl and Sodium phosphate dibasic were recorded in therange of 60° C. and 80° C. API transition peaks were detected at 180° C.and 193° C. (FIG. 87).

In a 1:1 mixture of amitriptyline HCl and Sodium bicarbonate, theendothermic transitions of sodium bicarbonate were recorded in the rangeof 150° C. to 180° C. (FIG. 88). No API transition peak was detected. Aphysical interaction was observed.

In a 1:1 mixture of Amitriptyline HCl and Sodium carbonate, theendothermic transitions of sodium carbonate were recorded in the rangeof 70° C. to 90° C. (FIG. 89). The API transition peak was detectedbetween 180° C. and 197° C. (onset at 182.8° C., ΔH=−33.8 J/g). A smallphysical interaction was observed.

In a 1:1 mixture of Amitriptyline HCl and Sodium phosphatedodecahydrate, the endothermic transitions were recorded in the range of40° C. to 112° C. (FIG. 90). No API transition peak was detected. Aphysical/chemical interaction was observed.

The endothermic transition of sodium phosphate in a 1:1 mixture ofAmitriptyline HCl and Sodium phosphate anhydrous was recorded in therange of 40° C. to 90° C. The API transition peak was detected between174° C. and 192° C. (onset at 179.8° C., ΔH=−222.8 J/g) (FIG. 91). Nophysical interaction was observed.

In summary, different types of interaction were observed among theexcipients and the API. A physical interaction was observed withMagnesium stearate and Sodium phosphate dibasic, probably because ofpartial API solubilization. A eutectic interaction was observed withPearlitol flash and Pearlitol 200 SO/Mannitol, due to the presence ofmannitol. The thermal transition of the API is completely shifted byexcipient complex formation of a eutectic. A physical interaction wasobserved with Sodium Stearyl fumarate, likely because of partial APIsolubilization or reactions at the particles' surfaces between the HCland Na counter ions. A physical interaction was observed with SodiumPhosphate dodecahydrate, also likely because of partial APIsolubilization. No interaction was observed with Stearic acid, Glyceroldibehenate, Unipure DW/Cornstarch partially pregelatinized, Silicon(colloidal), Crospovidone/Kollidon CL, Sodium carbonate, Sodiumbicarbonate, or Sodium Phosphate anhydrous. Table C summarizes the dataobserved.

TABLE C Interactions between API and excipients Excipient Mixture informulation (1:1 ratio) Sodium stearyl fumarate Physical interactionStearic acid No interaction Glycerol dibehenate No interaction Magnesiumstearate Physical interaction Pearlitol flash Eutectic interactionPearlitol 200 SO/Mannitol Eutectic interaction Unipure DW/Corn starchPartially no interaction Pregelatinized No interaction Crospovidone -Kollidon CL Silicon Colloidal/Aerosil 200 No interaction Sodiumphosphate dibasic Physical interaction Sodium bicarbonate No interactionSodium carbonate No interaction Sodium phosphate dodecahydrate Physicalinteraction Sodium phosphate anhydrous No interaction

1-22. (canceled)
 23. A pharmaceutical composition comprising a eutecticof mannitol and Amitriptyline HCl. 24-26. (canceled)
 27. Thepharmaceutical composition of claim 23, wherein the eutectic comprises75%±2% by weight Amitriptyline HCl and 25%±2% by weight mannitol. 28.(canceled)
 29. The pharmaceutical composition of claim 23 or 27, whereinthe Amitriptyline HCl is micronized Amitriptyline HCl.
 30. Thepharmaceutical composition of any one of claims 23, 27 or 29, furthercomprising a basifying agent.
 31. The pharmaceutical composition ofclaim 30, wherein the basifying agent is K₂HPO₄, Na₂HPO₄ or anhydroustrisodium citrate. 32-33. (canceled)
 34. A method of manufacturing theeutectic of the pharmaceutical composition of any one of claim 23, 27 or29-31, comprising mixing Amitriptyline HCl and mannitol or millingAmitriptyline HCl and mannitol.
 35. The method of claim 34, comprisingmilling Amitriptyline HCl and mannitol.
 36. The method of claim 35,wherein, the Amitriptyline HCl and mannitol are milled in a high sheargranulator.
 37. The method of claim 34, comprising mixing AmitriptylineHCl and mannitol.
 38. The method of claim 37, wherein the AmitriptylineHCl and mannitol are mixed via compression.
 39. The method of claim 38,wherein the Amitriptyline HCl and mannitol are compressed via rollercompaction.
 40. The method of any one of claims 34-39, wherein theAmitriptyline HCl is micronized Amitriptyline HCl. 41-44. (canceled)